The purpose of this grant is to identify susceptibility genes involved in the pathogenesis of keratoconus (KC). We will achieve our goal by: 1) refining criteria for the early detection of KC using videokeratography and wavefront Zernike variables; 2) comprehensively testing genes under newly identified linkage peaks generated through genome wide linkage scans of KC families, and performing comprehensive positional candidate gene association studies; and 3) characterizing specific genetic variants that predispose an individual to developing KC. We will study a cohort comprising: normal controls, patients with 'early' KC, KC 'suspect', and KC relatives with videokeratography and aberrometry in order to determine the best combination of variables that discriminate KC 'suspects' from normals. Study subjects will be followed longitudinally to determine which combination of variables is predictive of progression to KC, and thus define subclinical KC (Aim 1). After genome-wide linkage scan of multiplex KC families, we identified regions with significant or suggestive linkage on chromosomes 4, 5, 9, 11, 12, and 14, confirmed by subsequent fine mapping studies. To follow-up these positive linkage findings, we will conduct a comprehensive positional candidate gene association study by testing all genes in these regions with tagSNPs. Any positive association results will be tested in an independent sample for confirmation (Aim 2). Additionally, using newly identified criteria for defining subclinical markers for KC (combination of videokeratography and aberrometry), we will refine our linkage analysis on families with KC in an attempt identify new linkage peaks which may encompass new potential candidate genes for study. Genes identified by both genetic association studies and expression studies published in the literature to date will be prioritized for further study to identify specific genetic variants that contribute to the susceptibility of KC (Aim 3). Refining criteria for early detection of KC will provide the tools to prevent many patients from under- going unnecessary surgery and developing post-lasik ectasia, a significant public health issue. It will also facilitate identification of susceptibility genes for KC, which may provide an understanding of the mechanisms contributing to corneal thinning in KC. Ultimately, this work may improve our ability to treat KC and/or prevent the development of KC.